The federal Food and Drug Administration FDA and its European counterpart started reviews last year of these medicines, which came on the market less than a decade ago, after a study suggested a safety concern.

More than 25 million Americans and 33 million people in Europe have Type 2 diabetes, which impairs production or use of insulin to break down food into energy. That causes blood sugar to rise, putting them at risk of heart and other problems.

The drugs in question, called GLP-1 medicines, help spur insulin production after meals. Nine are approved in Europe and seven in the U.S., including include Merck’s Januvia and Janumet, Novo Nordisk’s Victoza and Bristol-Myers Squibb’s Byetta and Bydureon.

The labels for Byetta, Januvia and Janumet already have information about the possibility of pancreatic inflammation. A study of insurance records had suggested GLP-1 drugs could double this risk.

In July, the European Medicines Agency said its review had found no new evidence of pancreas problems.

On Wednesday, the New England Journal of Medicine published a report from scientists in Europe and at the FDA saying reviews of animal and human studies, plus new studies commissioned to look at this risk, had found no treatment-related adverse effects on the pancreas.

Although the review ‘‘provides reassurance,’’ the agencies ‘‘have not reached a final conclusion’’ about whether the drugs can cause pancreas problems and will ‘‘continue to investigate this safety signal,’’ the authors write.

Meanwhile, the drugs’ labels appear adequate, the agencies conclude.

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Key Finding

 

Combined comprehensive evaluation by the

FDA and EMA

 

• Included both nonclinical toxicology, clinical trial data and epidemiologic data of incretins

The FDA re-evaluated more than 250 toxicology studies conducted in nearly 18,000 healthy animals (15,480 rodents and 2,475 non-rodents)

 

• No findings of overt pancreatic toxic effects or pancreatitis upon microscopic review of toxicology studies

 

• Absence of drug-induced pancreatic tumors in rats and mice treated for up to 2 years (full life span), even at doses that exceed the level of human clinical exposure.

 

• No treatment related adverse effects on the pancreas were reported in 3 completed 3-month pancreatic toxicity studies in a rodent model of diabetes 

 

• 120 pancreatic histopathology slides from one of the 3 sponsor-conducted studies were subjected to independent and blinded examination by three FDA pathologist, coming to a concordant conclusion with respect to the sponsor’s report

 

• FDA performed own pancreatic toxicology studies with exenatide in both rodent disease and non-disease models (Mouse chemically induced pancreatitis, ZDF rat, C57BL/6 mice fed a high-fat diet 

 

• Assessment of clinical safety databases including data from

more than 200 trials (involving 41,000 participants, more than 28,000 exposed to incretin-based drug, 15,000 with exposure for 24 weeks or more and 8,500 exposed for 52 weeks and more) with small imbalances in premarketing trials, but with very small numbers.

 

• A number of observational studies have been reviewed and yielded inconsistent results (to some extent attributed to methodological shortcomings, including limited power, inadequate outcome validation, incomplete covariate ascertainment and inadequate confounding control)

 

IN CONCLUSION

 

• “Both agencies agree that assertions concerning a causal association between incretin-based drugs and pancreatitis or pancreatic cancer, as expressed recently in the scientific literature and in the media, are inconsistent with the current data.”

 

• “FDA and EMA have not reached a final conclusion at this time regarding such a causal relationship. Although the totality of the data that have been reviewed provided reassurance, pancreatitis will continue to be considered a risk associated with these drugs until more data are available”

 

• “FDA and EMA believe that the current knowledge is adequately reflected in the product information or labeling, and further harmonisation among products is planned in Europe.”

 
Egan AG, Blind E, Dunder K, de Graeff PA, Hummer BT, Bourcier T, Rosebraugh C. Pancreatic Safety of Incretin-based Drugs – FDA and EMA Assessment. N Engl J Med 2014;370:794-7. DOI: 10.1056/NEJMp1314078